Lithium enhances survival and regrowth of spinal motoneurons after ventral root avulsion

Abstract

BackgroundDuring the clinical treatment of the brachial plexus root avulsion (BPRA), reimplantation surgery can not completely repair the motor function of the hand because the axonal growth velocity of the spinal motoneurons (MNs) is too slow to re-innervate the intrinsic hand muscles before muscle atrophy. Here, we investigated whether lithium can enhance the regenerative capacity of the spinal MNs in a rat model of BPRA.ResultsThe avulsion and immediate reimplantation of the C7 and C8 ventral roots were performed and followed with daily intraperitoneal administration of a therapeutic concentrationof LiCl. After a 20 week long-term rehabilitation, the motor function recovery of the injured forepaw was studied by a grasping test. The survival and regeneration of MNs were checked by choline acetyltransferase (ChAT) immunofluorescence and by Fluoro-Gold (FG) retrograde labeling through the median and ulnar nerves of the ventral horn MNs. The number and diameter of the nerve fibers in the median nerve were assessed by toluidine blue staining. Our results showed that lithium plus reimplantation therapy resulted in a significantly higher grasping strength of the digits of the injured forepaw. Lithium plus reimplantation allowed 45.1% ± 8.11% of ChAT-positive MNs to survive the injury and increased the number and diameter of nerve fibers in the median nerve. The number of FG-labeled regenerative MNs was significantly elevated in all of the reimplantation animals. Our present data proved that lithium can enhance the regenerative capacity of spinal MNs.ConclusionsThese results suggest that immediate administration of lithium could be used to assist reimplantation surgery in repairing BPRA injuries in clinical treatment.

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

“…Results from Nouri et al suggest that lithium improves sciatic nerve regeneration after a traumatic lesion [72]. Additional evidence indicates that lithium exhibits synergistic effects in combined therapies with glial-derived neurotrophic factor in a model of rat sciatic nerve injury [23] and enhances the regenerative capacity of spinal motorneurons in a rat model of brachial plexus root avulsion [73]. To conclude, lithium’s pharmacology and biological effects in human patients have been extensively documented and its benefits on the central and peripheral nervous systems are seemingly clear.…”

Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

“…Other pharmacological approaches that have been implicated in reduction of glutamate‐induced excitotoxicity include the systemic application of Pre‐084, a Sigma‐1 receptor agonist, and lithium. Lithium increased motoneuron survival but not regeneration (Fu et al ., ), whereas daily injections of Pre‐084 leads to increased motoneuron survival, reduced astrogliosis and increased GDNF expression (Penas et al ., ).…”

“…Therefore most studies perform a DRG excision prior to avulsion and (graft) implantation (Wu et al, 1994b;Chai et al, 2000;Gu et al, 2005), resulting in sensory denervation. In a recent study, sparing of the DRG is described; however, the short length and fragility of the ventral root make manipulation and implantation surgically challenging (Fu et al, 2014). The lumbar ventral roots exit the spinal cord four to five segments proximal to their corresponding invertebral foramen, resulting in a longer segment of ventral root available for reimplantation and no obstruction due to the DRG.…”

“…Pharmacotherapeutic interventions following ventral root avulsion have primarily targeted the motoneurons in the ventral horn using neuroprotective or immune-modulatory agents ( Table 2). Neuroprotective approaches aimed at reducing glutamate excitotoxicity (Nogradi & Vrbova, 2001;Nagano et al, 2003;Bergerot et al, 2004;Nogradi et al, 2007;Pinter et al, 2010;Penas et al, 2011;Wu et al, 2013;Chew et al, 2014;Fu et al, 2014), preventing apoptosis by inhibition of the caspase pathway (Chan et al, 2001(Chan et al, , 2003Zhang et al, 2005) or the inhibition of NOS (Wu & Li, 1993;Zhou & Wu, 2006a).…”

Nerve Root Reimplantation in Brachial Plexus Injuries

“…Some drugs have been administered to minimize MN apoptosis and improve NR regeneration: resveratrol (3,4 0 ,5-trihydroxystilbene) [145], riluzole (2-amino-6-trifluoromethoxybenzothiazole) [8,69,121], lithium [146,147], minocycline [119], recombinant erythropoietin [118], FK506-tacrolimus [148][149][150][151], geldanamycin [152,153], acamprosate [67,154], ribavirin [154], N-acetyl cysteine [155] and glatiramer [156]. Some researchers have administered combinations such as acamprosate and ribavirin [154] or riluzole and GDNF [8].…”